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. 2016 Jul 27;8:61-6.
doi: 10.1016/j.ymgmr.2016.07.007. eCollection 2016 Sep.

Diagnosis of Adenylosuccinate Lyase Deficiency by Metabolomic Profiling in Plasma Reveals a Phenotypic Spectrum

Free PMC article
Case Reports

Diagnosis of Adenylosuccinate Lyase Deficiency by Metabolomic Profiling in Plasma Reveals a Phenotypic Spectrum

Taraka R Donti et al. Mol Genet Metab Rep. .
Free PMC article


Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive neurometabolic disorder that presents with a broad-spectrum of neurological and physiological symptoms. The ADSL gene produces an enzyme with binary molecular roles in de novo purine synthesis and purine nucleotide recycling. The biochemical phenotype of ADSL deficiency, accumulation of SAICAr and succinyladenosine (S-Ado) in biofluids of affected individuals, serves as the traditional target for diagnosis with targeted quantitative urine purine analysis employed as the predominate method of detection. In this study, we report the diagnosis of ADSL deficiency using an alternative method, untargeted metabolomic profiling, an analytical scheme capable of generating semi-quantitative z-score values for over 1000 unique compounds in a single analysis of a specimen. Using this method to analyze plasma, we diagnosed ADSL deficiency in four patients and confirmed these findings with targeted quantitative biochemical analysis and molecular genetic testing. ADSL deficiency is part of a large a group of neurometabolic disorders, with a wide range of severity and sharing a broad differential diagnosis. This phenotypic similarity among these many inborn errors of metabolism (IEMs) has classically stood as a hurdle in their initial diagnosis and subsequent treatment. The findings presented here demonstrate the clinical utility of metabolomic profiling in the diagnosis of ADSL deficiency and highlights the potential of this technology in the diagnostic evaluation of individuals with neurologic phenotypes.

Keywords: ADSL deficiency; ADSL, adenylosuccinate lyase; AICAR, aminoimidazole carboxamide ribotide; Global MAPSSM, Global Metabolomic Assisted Pathway Screen; IEM, inborn errors of metabolism; Intellectual disability; Metabolomic profiling; SAICAR, succinylaminoimidazole carboxamide ribotide; Succinyladenosine.


Fig. 1
Fig. 1
Adenylosuccinate lyase and purine nucleotide metabolism. Adenylosuccinate lyase catalyzes two pathways of purine nucleotide metabolism: de novo purine synthesis and the purine nucleotide cycle. Deficiency of ADSL results in blocks in these pathways, causing an increase in SAICAr, as well as an increase in S-Ado, as indicated by the red arrows. Abbreviations are as follows: PRPP, phosphoribosylpyrophosphate; SAICAR, succinylaminoimidazole carboxamide ribotide; SAICAr, succinylaminoimidazole carboxamide riboside; AICAR, aminoimidazole carbozamide ribotide; FAICAR, formyloaminoimidazole carboxamide ribotide; IMP, inosine monophosphate; S-AMP, adenylosuccinate; S-Ado, succinyladenosine; AMP, adenine monophosphate; XMP, xanthine monophosphate; GMP, guanine monophosphate; ADSL, adenylosuccinate lyase; AICAR TF, aminoimidazole carboxamide riboside transformylase; IMP CH, inosine monophosphate cyclohydrolase. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Elevated succinyladenosine levels support a diagnosis of ADSL deficiency. Succinyladenosine is a byproduct of the purine nucleotide cycle, involving conversion of adenylosuccinate (S-AMP) to adenylate (AMP). Succinyladenosine levels in the patient plasmas are the highest when compared to 625 unaffected samples. Elevation of succinyladenosine is indicative of ADSL deficiency. Red dots indicate the patients and open circles indicate outliers. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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